Anti-Inflammatory and Mydriatic Intracameral Solutions for Inhibition of Postoperative Ocular Inflammatory Conditions

ABSTRACT

The present invention provides methods for inhibiting postoperative inflammatory conditions following ophthalmologic surgical procedures by administering intraocularly during an ophthalmologic surgical procedure a solution including a nonsteroidal anti-inflammatory agent and an alpha-1 adrenergic mydriatic agent, such as a liquid irrigation solution of ketorolac and phenylephrine.

CROSS REFERENCE TO RELATED APPLICATION

The present application is a continuation of pending U.S. patentapplication Ser. No. 14/953,806, filed Nov. 30, 2015, which claims thebenefit of U.S. Provisional Application No. 62/086,133 filed Dec. 1,2014, priority from the filing dates of which are hereby claimed under35 U.S.C. § 120.

I. FIELD OF THE INVENTION

The present invention relates to methods of using liquid pharmaceuticalcompositions including a nonsteroidal anti-inflammatory agent and analpha-adrenergic mydriatic agent for intraocular administration duringan ophthalmologic surgical procedure to inhibit postoperativeinflammatory conditions.

II. BACKGROUND OF THE INVENTION

Ophthalmologic surgery necessarily results in trauma to delicateintraocular structures that induces prostaglandin synthesis and theinflammatory cascade. The resulting inflammation can result in theoccurrence of excess inflammation and associated postoperativeinflammatory conditions, particularly in subjects having a preoperativecondition placing them at elevated risk for postoperative inflammatoryconditions or that may experience an elevated level of surgical trauma.

Ocular surgery often requires the use of a physiologic irrigationsolution to facilitate the procedure and to protect and maintain thephysiological integrity of intraocular tissues. Examples ofophthalmologic surgical procedures typically requiring irrigationsolutions include cataract extraction and lens replacement andrefractive lens exchange procedures, corneal transplant procedures andvitreoretinal operations and trabeculectomy procedures for glaucoma.Throughout the intraocular surgery, a patient's pupil must besufficiently dilated to permit a clear operative field and to limit thetrauma that can be associated with the procedure. Pupil dilation(mydriasis) is typically achieved by dilating the eye preoperatively bytopical administration of a mydriatic agent.

During the surgery, as the tips of surgical tools are inserted into theanterior chamber of the eye and surgical trauma is induced, the irissphincter muscle tends to constrict (miosis), reducing the windowdefined by the pupil. If pupil diameter is not maintained adequatelythroughout the procedure, the risk of injuring structures within the eyeincreases and the required operating time is often prolonged. Clinicallysignificant reductions in pupil diameter are associated with an increasein procedure-related complications, including posterior capsule tears,retained lens fragments and vitreous leaks.

Many ophthalmologic surgeons may incorporate epinephrine into theintraocular irrigation solution to assist in the maintenance of pupildilation. While epinephrine is a alpha- and beta-adrenergic agonist,phenylephrine is an alpha-1 agonist that is sometimes administeredtopically prior to surgery to promote mydriasis, but phenylephrine isnot approved in the United States in a preservative- and bisulfite-freeform for intraocular administration.

It is also desirable to reduce postoperative pain and irritation forpatient comfort. Because of this, patients may be treated preoperativelyand/or postoperatively with a nonsteroidal anti-inflammatory drug(NSAID). Ketorolac is an NSAID that is commercially available inpreserved form for ocular use. Acular® from Allergan is a ketorolactromethamine solution that includes benzalkonium chloride 0.01% as apreservative, available in 3-mL and 6-mL dropper bottles. BedfordLaboratories also supplies ketorolac tromethamine in a concentrated form(15 mg or 30 mg in 1 mL or 60 mg or 300 mg in 10 mL) for injection forintravascular or intramuscular administration. Allergan supplies apreservative-free 0.45% ketorolac tromethamine ophthalmic solution,which is formulated with carboxymethylcellulose sodium, sodium chloride,sodium citrate dehydrate, in individual-use vials under the tradenameAcuvail®. Some ophthalmic surgeons also use topical NSAIDspreoperatively in an attempt to preempt intraoperative miosis. Thisapproach to miosis prevention is not optimal because intraoperativeirrigation solution washes out preoperatively delivered agents from theareas within the eye that are bathed by the irrigation solution.

Approved by FDA in 2014, OMIDRIA™ (phenylephrine and ketorolacinjection) 1%/0.3%), Omeros Corporation, is an alpha 1-adrenergicreceptor agonist and nonselective cyclooxygenase inhibitor indicated formaintaining pupil size by preventing intraoperative miosis and forreducing postoperative pain. OMIDRIA™ is added to standard irrigationsolution used during cataract surgery or intraocular lens replacement.OMIDRIA™ is not currently indicated for the reduction of postoperativeinflammation.

III. SUMMARY OF THE INVENTION

The present invention provides a method for inhibiting a postoperativeinflammatory condition following an ophthalmologic surgical procedure.The method includes identifying a subject with an elevated risk ofsuffering from a postoperative inflammatory condition, whichidentification may be made preoperatively based on a preexistingphysiologic condition or characteristic, prior treatment history, orpharmacologic history, and administering intraocularly to the subjectduring an ophthalmologic surgical procedure a solution including anonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergicreceptor agonist mydriatic agent in an intraocular irrigation carrier.The NSAID and the mydriatic agent are included in the solution inamounts sufficient to maintain intraoperative pupil diameter bypromoting mydriasis and inhibiting miosis, such as maintaining anintraoperative pupil diameter of at least 6.0 mm during the procedure,and a sufficient amount of the solution is administered for uptake of anamount of the NSAID in ocular tissues sufficient for inhibition ofcyclooxygenases for a period of at least six hours postoperatively,thereby inhibiting the postoperative inflammatory condition. In otherembodiments of the invention, the identification of an elevated risk ofpostoperative inflammation may occur during the procedure based on thenature of trauma incurred during the procedure. In still otherembodiments, the identification of an elevated risk of a postoperativeinflammatory condition may be made intraoperatively and/orpreoperatively.

Suitable NSAIDs for use in the solution administered in accordance withthe present invention include flurbiprofen, suprofen, diclofenac,ketoprofen, ketorolac, indomethacin, nepafenac and bromfenac, andsuitable alpha-1 adrenergic receptor agonists include phenylephrine,epinephrine, oxymetazoline and naphazoline. In a preferred embodiment ofthe invention, the NSAID is ketorolac and the mydriatic agent isphenylephrine. In another embodiment the solution includes phenylephrineat a concentration of from 240 to 720 μM and ketorolac at aconcentration of from 44 to 134 μM. The phenylephrine and ketorolac maybe suitably included at a molar ratio of from 3:1 to 10:1 phenylephrineto ketorolac.

In one embodiment of the present invention, administration of thesolution results in at least 85%, and preferably at least 90%,inhibition of baseline cyclooxygenase-1 (COX-1) and cyclooxygenase-2(COX-2) activity in ocular tissues for a period of at least six hourspostoperatively. In another embodiment of the present invention,administration of the solution results in at least 85%, and preferablyat least 90%, inhibition of baseline COX-1 and COX-2 activity in oculartissues for a period of at least seven hours postoperatively. In anotherembodiment of the present invention, administration of the solutionresults in at least 85% inhibition of baseline COX-1 and COX-2 activityin ocular tissues for a period of at least eight hours postoperatively.In another embodiment of the present invention, administration of thesolution results in at least 90% inhibition of baseline COX-1 and COX-2activity in ocular tissues for a period of at least eight hourspostoperatively. In still another embodiment, administration of thesolution results in at least 85% inhibition of baseline COX-1 and COX-2activity in ocular tissues for a period of at least ten hourspostoperatively.

The method of the present invention may be used in any ophthalmologicsurgical procedure associated with a risk of postoperative inflammation,including procedures requiring pupil dilation and associated withpostoperative inflammation, such as cataract extraction and lensreplacement, refractive lens exchange, vitrectomy, retinalphotocoagulation, retinal detachment repair, macular hole repair,retroiris tumor or mass removal, posterior sclerotomy and opticneurotomy, or in connection with the inhibition of inflammatoryconditions resulting from intravitreal injections. In some embodiments,the solution of the present invention is administered to irrigateintraocular tissues during the procedure, such as continuouslythroughout the procedure. In other embodiments, solution of the presentinvention is administered by intraocular injection as part of theprocedure. In still other embodiments, the solution of the presentinvention is administered by irrigation of intraocular tissues duringthe procedure followed by intraocular injection of a bolus of thesolution at the end of the procedure. In still another embodiment, thesolution of the present invention is administered by postoperativeinjection of a bolus of the solution at the end of the procedure, forexample following the identification of the patient being at risk of apostoperative inflammatory condition due to trauma incurredintraoperatively. In still another embodiment, the solution isadministered by intraocular injection preoperatively, intraoperativelyand/or postoperatively.

In another aspect of the invention, the method is used in a procedureselected from vitrectomy, retinal photocoagulation, retinal detachmentrepair, macular hole repair, retroiris tumor or mass removal, posteriorsclerotomy and optic neurotomy, or in connection with the inhibition ofinflammatory conditions resulting from intravitreal injections.

Postoperative inflammatory conditions inhibited by the methods of thepresent invention include, for example, toxic anterior-segment syndrome,cystoid macular edema including nonpseudophakic cystoid macular edemaand pseudophakic (Irvine-Gass) cystoid macular edema, acuteendophthalmitis, posterior capsule opacification, anterior capsulecontraction, herpes simplex virus keratitis after cataract surgery,postsurgical hypotony, nylon suture toxicity, long-term cornealendothelial cell loss after cataract surgery, corneal edema, irischafing, corneo-retinal inflammatory syndrome, scleritis, episcleritis,vitreous wick syndrome, post-operational acute iridocyclitis, uveitis,epiretinal deposits after cataract extraction, reiterative membranousproliferation with giant-cell deposits, toxic vitreitis, posteriorsynechia, postoperative intraocular fibrin formation, incisionalfibrosis, complications of macular hole surgery, choroidal effusion, andhypopyon.

In other embodiments, the subject is identified as having an elevatedrisk of a postoperative inflammatory condition because of a preoperativephysiologic condition or characteristic including small pupil diameter(e.g., a dilated preoperative pupil diameter of less than 6 mm), floppyiris syndrome, uveitis, retinal vein occlusion, epiretinal membrane,advanced age (e.g., over 65, elderly or geriatric), diabetes mellitus,diabetic macular edema, diabetic retinopathy, macular degeneration, orsystemic hypertension; a preoperative treatment history includingprevious ocular surgery or pharmacologic treatment with analpha-1-adrenergic receptor antagonist or latanoprost; surgical traumaincluding posterior capsule rupture, secondary capsulotomy, irisincarceration, retained lens material, or vitreous loss; and thesurgical placement of nylon sutures, iris-fixated intraocular lens or ananterior chamber intraocular lens.

In a further aspect of the invention, the subject is identified ashaving an elevated risk of a postoperative inflammatory conditionbecause of a preoperative physiologic condition or characteristicselected from small pupil diameter (e.g., a dilated preoperative pupildiameter of less than 6 mm), floppy iris syndrome, uveitis, retinal veinocclusion, epiretinal membrane, diabetic macular edema, diabeticretinopathy, macular degeneration, or systemic hypertension; apreoperative treatment history including previous ocular surgery orpharmacologic treatment with an alpha-1-adrenergic receptor antagonistor latanoprost; surgical trauma including posterior capsule rupture,secondary capsulotomy, iris incarceration, retained lens material, orvitreous loss; and the surgical placement of nylon sutures, iris-fixatedintraocular lens or an anterior chamber intraocular lens.

The present invention also provides a method for inhibiting apostoperative inflammatory condition following an ophthalmologicsurgical procedure by identifying a subject with a physiologic risk ofsuffering from a postoperative inflammatory condition and administeringintraocularly to the subject during an ophthalmologic surgical procedurea solution including a nonsteroidal anti-inflammatory drug (NSAID) andan alpha-1 adrenergic receptor agonist mydriatic agent in an intraocularirrigation carrier, wherein the NSAID and the mydriatic agent areincluded in the solution in amounts sufficient for the maintenance ofintraoperative pupil diameter due to the intraoperative promotion ofmydriasis by the mydriatic agent and the intraoperative inhibition ofmiosis by the NSAID, thereby reducing intraoperative trauma, and for theinhibition of the postoperative inflammatory condition by theintraoperative and postoperative anti-inflammatory effect of the NSAID.

The present invention provides a method for inhibiting a postoperativeinflammatory condition following an ophthalmologic surgical procedure byintraocular administration during an ophthalmologic surgical procedure,to a subject at risk of a postoperative inflammatory condition, asolution including a nonsteroidal anti-inflammatory drug (NSAID) and analpha-1 adrenergic receptor agonist mydriatic agent in an intraocularirrigation carrier. The NSAID and the mydriatic agent are included inthe solution in amounts sufficient to maintain intraoperative pupildiameter by promoting mydriasis and inhibiting miosis, and a sufficientamount of the solution is administered for uptake of an amount of theNSAID in ocular tissues sufficient for inhibition of cyclooxygenases fora period of at least six hours postoperatively, thereby inhibiting thepostoperative inflammatory condition.

IV. BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will now be described in greater detail, by way ofexample, with reference to the accompanying drawings in which:

FIGS. 1-3 provide results from the clinical studies of Example 1.

FIG. 1 illustrates the mean (±SEM) change from baseline in mean pupildiameter (PD) over time to the end of surgery. Pupil diameters weremeasured at 1-minute intervals from baseline to the end of the procedureand at the end of cortical cleanup from a video recording of thesubject's surgery.

FIG. 2 illustrates the maximum intraoperative pupil constriction at anytime during surgery resulting from the studies.

FIG. 3 illustrates the mean ocular pain visual analog scale (VAS) scoresduring the early postoperative period (full analysis set population).

FIGS. 4-7 provide results from the intracameral dog study of Example 2,and illustrate the mean concentrations of ketorolac in ocular tissues offemale dogs at specified time points after the intracameral dosing ofphenylephrine 1.0%/ketorolac 0.3% injection in balanced salt solution.

FIG. 4 shows ketorolac concentrations in the cornea, lens capsule,iris-ciliary body (ICB), aqueous humor, and anterior sclera.

FIG. 5 shows ketorolac concentrations in the bulbar and palpebralconjunctiva.

FIG. 6 shows ketorolac concentrations in the vitreous humor, retina,choroid-RPE (peripheral), choroid-RPE (tapetum), and posterior sclera.

FIG. 7 shows the mean percent inhibition of COX-1 and COX-2 in retinaltissues at t=0 through t=10 hours.

V. DETAILED DESCRIPTION

The present invention provides a method for inhibiting a postoperativeinflammatory condition following an ophthalmologic surgical procedure byintraocular administration during an ophthalmologic surgical procedure,to a subject at risk of a postoperative inflammatory condition, asolution including a nonsteroidal anti-inflammatory drug (NSAID) and analpha-1 adrenergic receptor agonist mydriatic agent in an intraocularirrigation carrier. The NSAID and the mydriatic agent are included inthe solution in amounts sufficient to maintain intraoperative pupildiameter by promoting mydriasis and inhibiting miosis, thereby reducingthe potential for inflammation-inducing trauma to intraocularstructures. A sufficient amount of the solution is administered foruptake of an amount of the NSAID in ocular tissues sufficient forinhibition of cyclooxygenases for a period of at least six hourspostoperatively, thereby inhibiting or reducing the likelihood orseverity of the postoperative inflammatory condition.

Ophthalmologic Surgical Procedures

The present invention may be utilized in a variety of ophthalmologicsurgical procedures that are associated with the occurrence ofpostoperative inflammatory conditions, including anterior segmentprocedures performed in the anterior chamber or posterior chamber of theeye, and procedures performed in the posterior segment of the eye, suchas retinal procedures. In many cases the procedure is an intracameralprocedure. Suitably the ophthalmologic surgical procedure during whichthe method of the present invention is used is a procedure requiringdilation or mydriasis of the pupil, to provide the surgeon an expandedoperative field and visualization of intraocular structures through thedilated pupil. In accordance with the present invention, the solution isadministered intraocularly by irrigation and/or injection during theprocedure to maintain pupil diameter by promoting mydriasis andinhibiting miosis, thereby reducing surgical trauma to the iris andintraocular structures manipulated through the iris. The solution of thepresent invention may be administered into the anterior segment of theeye, in particular into the anterior chamber or posterior chamber of theeye, or into the posterior segment of the eye.

Examples of procedures requiring pupil dilation and associated withpostoperative inflammation suitable for practice of the presentinvention include cataract extraction and lens replacement (CELR),refractive lens exchange (RLE), vitrectomy, retinal photocoagulation,retinal detachment repair, macular hole repair, retroiris tumor or massremoval, posterior sclerotomy and optic neurotomy. CELR and RLE mayinvolve femtosecond or scalpel incision, phacoemulsification for lensremoval and intraocular lens (IOL) replacement. The present inventionmay also be used in connection with the inhibition of inflammatoryconditions resulting from intravitreal injection, by injecting thesolution of the present invention together or concurrently with, orimmediately preceding or following, the injection of one or more othertherapeutic agents, such as an anti-vascular endothelial growth factor(anti-VEGF) such as ranibizumab.

Ophthalmic surgeons typically use preoperative treatment with mydriaticmedications to dilate the pupil before surgery. Behndig, A., et al.,“Intracameral mydriatics in cataract surgery,” Cataract Surgery, ZaidiF. (ed.), Rijeka, Croatia: InTech 2013:149-172. The larger and longerthe pupil stays dilated with one or more mydriatic agents, the easierand less risky the procedure. Pupil constriction during surgery makesthe procedure more difficult and increases the risk of additionalcomplications. (Behndig 2013)

Postoperative Inflammation

Most cataract procedures are routine and uncomplicated. Patalano, V. J.,“The risks and benefits of cataract surgery,” Digital Journal ofOphthalmology, http://www.djo.harvard.edu/site.php?url=/patients/pi/408,Accessed Jun. 26, 2014; A.D.A.M., Inc., “Cataracts In-depth report,” TheNew York Times,http://www.nytimes.com/health/guides/disease/cataract/print.html,accessed Jun. 26, 2014. But the occurrence of intraoperativecomplications is often unpredictable and estimated to be associated with3.8% of cataract procedures in the United States. (Patalano 2014);Greenberg, P. B., et al., “Prevalence and predictors of ocularcomplications associated with cataract surgery in United Statesveterans,” Ophthalmology 118(3):507-514 (2011).

Intraoperative miosis makes the cataract surgical procedure moredifficult by shrinking the surgeon's visual field and working space.(Behndig 2013) A small pupil during surgery is associated with increasedrisk of intraoperative complications, including posterior capsulerupture and vitreous loss. Artzen, D., et al., “Capsule complicationduring cataract surgery: Case-control study of preoperative andintraoperative risk factors: Swedish Capsule Rupture Study Group report2,” J Cataract Refract Surg 35(10):1688-1693 (2009); Zare, M., et al.,“Risk factors for posterior capsule rupture and vitreous loss duringphacoemulsification,” J Ophthalmic Vis Res. 4(4):208-212 (2009). Reducedvisibility and room for surgical maneuvering may also lead to anincreased chance of losing a portion of the lens or the whole lensnucleus into the vitreous cavity (dropping the nucleus) or causinginjury to the iris. (Behndig 2013)

Intraoperative miosis is frequently associated with intraoperativefloppy iris syndrome (IFIS). Eyes with IFIS have loose, billowy iristissue with increased risk of prolapse and pupil constriction duringsurgery. Chang, D. F., Campbell, J. R., “Intraoperative floppy irissyndrome associated with tamsulosin,” J Cataract Refract Surg31(4):664-673.22 (2005); Chang, D. F., et al., “Prospective multicenterevaluation of cataract surgery in patients taking tamsulosin (Flomax)”Ophthalmology 114(5):957-964 (2007). The number of IFIS cases is knownto be especially high among patients who have received treatment with anα1-adrenergic receptor antagonist, such as tamsulosin (Flomax). (Chang2005); Haridas, A, et al., “Intraoperative floppy iris syndrome (IFIS)in patients receiving tamsulosin or doxazosin-a UK-based comparison ofincidence and complication rates” Graefes Arch Clin Exp Ophthalmol251(6):1541-1545 (2013). Tamsulosin is used for the treatment ofpatients with benign prostatic hyperplasia (noncancerous enlargement ofthe prostate). Significant intraoperative miosis has been shown to occurin more than 70% of these high-risk patients, even when surgery wasperformed by highly experienced cataract surgeons. (Chang 2007).

Surgical trauma causes intraocular inflammation, even if the procedureis routine and uncomplicated. Lobo, C., “Pseudophakic cystoid macularedema,” Ophthalmologica 227(2):61-67 (2012); Miyake, K., Ibaraki, N.,“Prostaglandins and cystoid macular edema” Surv Ophthalmol 2(47 suppl1):S203-S18 (2002). Inflammation usually begins in the anterior chamber,either at the site of surgical entry or due to direct mechanicalstimulation of intraocular structures such as the iris or ciliary body.Early inflammatory pathways are self-perpetuating, which means thatinflammation initially grows in intensity and spreads from the anteriorchamber to the vitreous and retina. (Lobo 2012); (Miyake 2002).

Inflammation is associated with vessel dilation and vascular leakage.When the eye is inflamed after surgery, retinal vessels leak and theaccumulation of excess fluid causes retinal swelling, or edema. (Lobo2012); (Miyake 2002). Swelling can include the macula, a specializedzone of the central retina that provides sharp detailed vision used intasks like reading or driving. Retinal swelling that involves the maculais called macular edema. Cystoid macular edema (CME) is defined by thepresence of anatomically distinct fluid pockets, or cysts. Ismail, R.,Sallam, A., “Complications associated with cataract surgery,” CataractSurgery, Zaidi F. (ed.), Rijeka, Croatia: InTech 2013:221-244.Inflammation and increased levels of intraocular prostaglandins aftercataract surgery have been identified as a cause of CME, and there is anassociation between severe anterior ocular inflammation and postsurgicalCME. Rossetti, L., Autelitano, A., “Cystoid macular edema followingcataract surgery,” Opin Ophthalmol 11:65-72 (2000).

Cystoid macular edema (CME) is a primary cause of reduced visionfollowing both cataract and successful vitreoretinal surgery.Loewenstein, A., Zur, D., “Postsurgical Cystoid Macular Edema,” MacularEdema, Dev Ophthalmol., Coscas, G. (ed.), Basel, Karger 2010:148-159.CME also remains a problem following capsulotomy, penetratingkeratoplasty, scleral buckling, filtering procedures, and panretinalphotocoagulation. (Loewenstein 2010); Shimura, M., et al., “Panretinalphotocoagulation induces pro-inflammatory cytokines and macularthickening in high-risk proliferative diabetic retinopathy,” GraefesArch Clin Exp Ophthalmol 11:65-72 (2000). Estimates of postoperative CMEincidence depend on the definition and the method of detection. Studiesestimate the prevalence of CME after cataract surgery to be between 4%and 20%. Wielders, L., et al., “Prevention of CME after cataractsurgery,” Cataract Refract Surg Today Eur. 53-55 (2013). CME does notlead to decreased vision in every case, or decreased vision may be minorand imperceptible to the patient. Clinically significant macular edemais associated with visual impairment and estimated to occur in up to5.8% of eyes after cataract surgery. (Lobo 2012); (Wielders 2013).

An in vivo study evaluated prostaglandin accumulation in the aqueoushumor following paracentesis in rabbits as a model of ocular surgicaltrauma. The concentration of PGE2 in the aqueous humor peaked at onehour following paracentesis and remained substantially elevated forseven hours post paracentesis, approaching baseline levels 48 hoursafter surgical insult. Graff, G. et al., “Transient loss ofprostaglandin synthetic capacity in rabbit iris-ciliary body followinganterior chamber paracentesis,” Ocular Immunology and Inflammation6(4):227-238 (1998). This study illustrates that once the inflammatorycascade is initiated during ocular surgical trauma, prostaglandin levelsremain elevated for a prolonged period, potentially leading to undesiredpostoperative conditions associated with excess inflammation.

Postoperative Inflammatory Conditions

Excess inflammation induced by ophthalmologic surgery can result in anumber of undesired postoperative conditions, and the methods andcomposition of the present invention may be used to inhibit or reducethe severity or incidence of these conditions. Toxic anterior segmentsyndrome (TASS) is an acute postoperative inflammatory reaction in whicha noninfectious substance enters the anterior segment and induces toxicdamage to the intraocular tissues. Almost all cases occur afteruneventful cataract surgery, and, more recently, it has been reportedafter phakic intraocular lens implantation. This syndrome was previouslydefined by other names, such as sterile endophthalmitis or postoperativeuveitis of unknown cause. Furthermore, a condition termed toxicendothelial cell destruction (TECD) syndrome has been described and isbelieved to be a variant of TASS. Nonsteroidal anti-inflammatory dropshave been shown to be a helpful adjunct in several cases of TASS,supporting that TASS is mediated by inflammation. Al-Ghouri, A. R.,M.D., “Toxic Anterior Segment Syndrome,”http://emedicine.medscape.com/article/1190343-overview, accessed Nov.23, 2014.

Cystoid macular edema (CME) is a painless condition in which swelling orthickening occurs of the central retina (macula) and is usuallyassociated with blurred or distorted central vision. Less commonsymptoms include metamorphopsia, micropsia, scotomata, and photophobia.CME is a relatively common condition and is frequently associated withvarious ocular conditions, such as age-related macular degeneration(AMD), uveitis, epiretinal membrane, vitreomacular traction, diabetes,retinal vein occlusion, medicine-related, or following ocular surgery.When CME develops following cataract surgery and its cause is thought tobe directly related to the surgery, it is referred to as Irvine-Gasssyndrome or pseudophakic CME. Medical therapy of Irvine-Gass syndromeincludes NSAIDs, corticosteroids, and carbonic anhydrase inhibitors.Recent advances in cataract surgery, such as phacoemulsification,small-incision surgery and advances in foldable intraocular lenses, haveresulted in the decrease of physical trauma associated with cataractsurgery. The decrease in the physical surgical trauma decreases therelease of prostaglandins, which are the main players in postoperativeocular inflammation. However, postoperative inflammation continues to bea cause of patient discomfort, delayed recovery and, in some cases,suboptimal visual results. Left untreated, this inflammation mightinterfere with patients' rehabilitation and/or contribute to thedevelopment of other complications, such as cystoid macular edema.Topically applied NSAIDs are commonly used in the management andprevention of non-infectious ocular inflammation and cystoid macularedema following cataract surgery. Colin, J., “The Role of NSAIDs in theManagement of Postoperative Ophthalmic Inflammation,” Drugs67(9):1291-308 (2007).

Although the most common cause of cystoid macular edema (CME) is due toIrvine-Gass syndrome of CME after cataract extraction or otherintraocular surgery, i.e., pseudophakic cystoid macular edema, numerousother conditions are associated with the clinical appearance offluid-filled cystoid spaces in the macular region, i.e., nonpseudophakiccystoid macular edema. CME is a final common pathway of many intraoculardiseases, usually involving the retinal vasculature. The appearance candiffer somewhat, depending on the etiology; however, CME can appear as anonspecific clinical finding. If the cause of CME is not obvious,detailed ophthalmoscopy and, occasionally, ancillary testing may benecessary to identify the cause. The most common drugs used to treat CMEinclude steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), andacetazolamide. Roth, D. B., M.D., “Nonpseudophakic Cystoid MacularEdema,” http://emedicine.medscape.com/article/1225735-overview#showall,accessed Nov. 23, 2014.

Inflammation also appears to play a role in acute postoperativeendophthalmitis, and the inventors believe that the present inventionmay be suitable for ameliorating this condition. The use of intravitrealdexamethasone in the treatment of acute postoperative endophthalmitisremains controversial. Clinicians have used this short-actingcorticosteroid to inhibit the inflammatory effects of bacterialendotoxins, host factors, and antibiotics. In a rabbit model of virulentinfectious endophthalmitis, dexamethasone was shown to decreaseelimination of intraocular vancomycin through the trabecular meshwork,suggesting a new potential benefit to steroid administration. Clark, W.L., M.D., “Postoperative Endophthalmitis Treatment & Management,”http://emedicine.medscape.com/article/1201260-treatment, accessed Nov.23, 2014. Nonsteroidal anti-inflammatory drugs may offer equivalentanti-inflammatory efficacy (for both postoperative inflammation andcystoid macular edema) without the typically corticosteroid-associatedadverse events. Rowen, S., “Preoperative and Postoperative MedicationsUsed for Cataract Surgery,” Curr Opin Ophthalmol. 10(1):29-35 (1999).

The present invention may also suitably be used to inhibit postoperativeposterior capsule opacification or anterior capsule contraction. Inabout 20 percent of patients, the posterior portion of the capsulebecomes hazy some time during cataract surgery recovery or even monthslater, causing posterior capsule opacification. Posterior capsuleopacification occurs because lens epithelial cells, remaining aftercataract surgery, have grown on the capsule. Knobbe, C. A., M.D.,“Cataract Surgery Complications,”http://www.allaboutvision.com/conditions/cataract-complications.htm,accessed Nov. 23, 2014. Sustained-release celecoxib (an NSAID) fromincubated acrylic intraocular lenses has been shown to suppress lensepithelial cell growth in an ex vivo model of posterior capsule opacity.Davis, J. L., et al., “Sustained-release Celecoxib From IncubatedAcrylic Intraocular Lenses Suppresses Lens Epithelial Cell Growth in anEx Vivo Model of Posterior Capsule Opacity,” J Ocul Pharmacol Ther.28(4):359-68 (2012).

The present invention may also be suitably used to inhibit herpessimplex virus keratitis after cataract surgery. Ocular infection withherpes simplex virus (HSV) results in a blinding immunoinflammatorystromal keratitis (SK) lesion. Early preclinical events includepolymorphonuclear neutrophil (PMN) infiltration and neovascularizationin the corneal stroma. HSV infection of the cornea has been demonstratedto result in the upregulation of the cyclooxygenase 2 (COX-2) enzyme.The induction of COX-2 by HSV infection is a critical event, sinceinhibition of COX-2 with a selective inhibitor has been shown to reducecorneal angiogenesis and SK severity. The administration of a COX-2inhibitor has been shown to result in reduced PMN infiltration into thecornea as well as diminished corneal vascular endothelial growth factorlevels, likely accounting for the reduced angiogenic response. Biswas,P. S., et al, “Role of Inflammatory Cytokine-induced Cyclooxygenase 2 inthe Ocular Immunopathologic Disease Herpetic Stromal Keratitis,” J Virol79(16):10589-600 (2005).

The nonsteroidal anti-inflammatory drug ketorolac may preventpost-surgical hypotony due to cyclooxygenase products that are releasedduring cataract surgery and other procedures, indicating further utilityfor the present invention. A study evaluating inhibition of PGE2production by ketorolac, bromfenac and nepafenac in patients undergoingphacoemulsification demonstrated that ketorolac 0.45% achieved thegreatest inhibition of PGE2 compared to nepafenac 0.1% and bromfenac0.09. Bucci, F. A., Jr., et al., “Prostaglandin E2 Inhibition ofKetorolac 0.45%, Bromfenac 0.09%, and Nepafenac 0.1% in PatientsUndergoing Phacoemulsification,” Adv Ther 28(12):1089-95 (2011). Thepossibility of an acute increase in intraocular pressure (IOP) followinglaser iridotomy is well known. A study has shown that laser irradiationof the iris itself can also cause ocular hypotony, so that thisphenomenon may be another explanation of the IOP response afterperipheral iridoplasty. Kim, Y. Y., et al., “Biphasic IntraocularPressure Response to Laser Irradiation of the Iris in Rabbits,”Ophthalmic Res 27(4):243-8 (1995).

Nylon suture toxicity may also result in postoperative inflammation andbe suitably inhibited by use of the present invention. A cluster ofsymptoms and signs that developed in 10 of 105 consecutive patients(9.5%) who underwent uncomplicated planned extracapsular cataractextraction (ECCE) with posterior chamber intraocular lens (PC IOL)implants has been reported as appearing to be related to wound closure.These signs and symptoms included foreign body sensation, conjunctivalinjection and infiltrates localized to the scleral wound, and scleralexcavation underlying the running 10-0 nylon suture possibly resultingfrom localized scleral edema. The time of clinical presentation rangedfrom 1 to 6 weeks. Conjunctival stains demonstrated eosinophils andpolymorphonuclear leukocytes in some cases. Gram stains, conjunctivalcultures, and results of suture toxicology studies were negative.Balyeat, H. D., et al., “Nylon Suture Toxicity After Cataract Surgery,”Ophthalmology 95(11):1509-14 (1988).

Cataract surgery can in some cases result in long-term cornealendothelial cell loss, while vitrectomy may result in corneal edema,both conditions that may be inhibited by the present invention.Three-day and 1-day dosing of ketorolac has been shown to reducesurgical time, phacoemulsification time and energy, and endothelial cellloss and improved visual acuity in the immediate postoperative periodcompared with 1-hour predosing or use of a placebo. Donnenfeld, E. D.,et al., “Preoperative Ketorolac Tromethamine 0.4% in PhacoemulsificationOutcomes: Pharmacokinetic-response Curve,” J Cataract Refract Surg.32(9):1474-82 (2006); Hiraoka, M., et al., “Factors Contributing toCorneal Complications after Vitrectomy in Diabetic Patients,” Jpn JOphthalmol. 45(5):492-5 (2001). Ketorolac tromethamine 0.5% ophthalmicsolution has been shown to be effective and well-tolerated incontrolling postoperative inflammation. Simone, J. N., “Comparison ofthe Efficacy and Safety of Ketorolac Tromethamine 0.5% and PrednisoloneAcetate 1% after Cataract Surgery,” J Cataract Refract Surg.25(5):699-704 (1999).

Intraocular lens implantation may be associated with a corneo-retinalinflammatory syndrome that leads to corneal decompensation and cystoidmacular edema. The inflammatory aspects often do not appear striking butmanifest as mild ciliary flush, mild flare, moderate cells in theanterior chamber, and moderate vitritis. The cornea will decompensate inthe presence of endothelial cell counts which are sufficient to maintaincorneal clarity in the non-inflamed eye. Metal-looped lenses and poorlypolished lenses cause iris chafing and capillary leakage, which increasethe severity of this syndrome. It is postulated that intraocular surgeryinitiates an inflammatory response that is augmented by certaincomponents of intraocular lenses. The mediation for this increasedinflammatory response may be inhibited by both steroidal andnon-steroidal anti-inflammatory agents. The presence of white bloodcells and their products, such as lysosomal enzymes, may be sufficientto perpetuate the inflammatory response and cause damage to abnormal andnormal cells. The presence of protein and its immune components, as wellas complement, may be involved in this syndrome. Obstbaum, S. A., etal., “Cystoid Macular Oedema and Ocular Inflammation. The Corneo-RetinalInflammatory Syndrome,” Trans Ophthalmol Soc UK. 99(1):187-91(1979).

Postsurgical scleritis and episcleritis may also be inhibited by use ofthe present invention. A number of cases of necrotic sclerokeratitisfollowing eye surgery have been reported in recently publishedliterature. The condition was presumably triggered by surgicalinflammation and caused by localized occlusive vasculitis: in one casedeposits of immune complexes in vessel walls were demonstrated. Clinicalexamination shows disappearance of vessels in affected sclera, togetherwith tissue necrosis. Gregersen, E., et al., “NecrotizingSclerokeratitis Following Cataract Extraction,” Klin Monbl Augenheilkd.193(6):642-4 (1988). In a report of 21 cases, out of a total of 682cataract patients, of surgically induced diffuse scleritis (SIDS)following planned extracapsular cataract extraction with intraocularlens insertion, the mean age was found to be significantly lower in thepatients with SIDS (mean 62.5 years; SD 13.68) when compared with thenon-scleritic group (mean 73.6 years; SD 10.2; Mann-Whitney U-test,p=0.0003). There was an association of SIDS with general anesthesia(chi-squared test, p=0.0008). Twenty of the 21 patients with SIDSresponded to oral non-steroidal anti-inflammatory agents with goodvisual result. Scott, J. A., et al., “Surgically Induced DiffuseScleritis Following Cataract Surgery,” Eye (Lond). 8 (Pt 3):292-7(1994).

Vitreous wick syndrome occurs after eye surgery and consists ofmicroscopic wound breakdown, followed by a vitreous prolapse thatdevelops into a vitreous wick, and may also be suitably inhibited bypractice of the present invention. Vitreous wick syndrome develops inthe setting of trauma, either iatrogenic or noniatrogenic. Vitreous wicksyndrome of iatrogenic origin usually follows anterior-segment surgery,though it may also follow subtenon injection and muscle surgery. Cornealwound healing has been documented to be slower on the endothelial side(inner layers). Poor suturing technique is implicated as a major factorfor wound breakdown. Tightly compressed corneal wound edges maydemonstrate puckering and also may lead to enlargement of suture tracts,promoting tissue necrosis within the suture loop. Once communicationbetween the posterior wound gap and the anterior wound defect occurs(subsequent to tissue necrosis from tight sutures), anterior aqueousfluid may egress; vitreous incarceration may also occur, producing thevitreous wick. Occasionally, complete sloughing of strangulated tissuewithin the suture loop may occur. Rogue, M. R., M.D., M.B.A., F.P.A.O,“Vitreous Wick Syndrome.,”http://emedicine.medscape.com/article/1230457-overview#a0101, accessedNov. 23, 2014. A study comparing the force required to separate cornealwounds after topical applications of nonsteroidal anti-inflammatorydrugs or corticosteroids found that steroid treatment caused weakercorneal wound scars than did NSAIDs. McCarey, B. E., et al., “CornealWound Healing Strength with Topical Antiinflammatory Drugs,” Cornea14(3):290-4 (1995).

Post-operational acute iridocyclitis, or post-surgical inflammation ofthe iris and ciliary body, also provides a treatment opportunity for thepresent invention. Evaluation of the adjunctive use of nonsteroidalanti-inflammatory drugs for the treatment of chronic iridocyclitis in 14patients has been reported, eight of whom had juvenile rheumatoidarthritis and six with idiopathic iridocyclitis. In all patients, theactivity of the iridocyclitis improved with the addition of NSAIDs totheir treatment regimens, permitting reduction in the dose ofcorticosteroid drugs. These data suggest that NSAID therapy may have anadjunctive role in the treatment of chronic iridocyclitis in childhood.Olson, N.Y., et al., “Nonsteroidal anti-inflammatory drug therapy inchronic childhood iridocyclitis,” Am J Dis Child 142(12):1289-92 (1988).Cataract is an early complication of juvenile idiopathicarthritis-associated uveitis. Under strict control of uveitis, IOLimplantation is an important alternative in visual rehabilitation forthis type of patient. Control of uveitis with NSAIDs before, during andafter cataract surgery presents a further utility for the presentinvention. Kotaniemi, K., et al., “Intraocular Lens Implantation inPatients with Juvenile Idiopathic Arthritis-Associated Uveitis,”Ophthalmic Res. 38(6):318-23 (2006).

The present invention may additionally be used to inhibit inflammationdue to epiretinal deposits after cataract extraction. In a report of twopatients identified with epiretinal deposits after cataract extractionwhere the posterior capsule barrier was breached, inflammation was foundto be limited to the posterior segment, and investigative work-up forinfective causes was negative. Behera, U. C., “Epiretinal Deposits PostCataract Extraction,” Retin Cases Brief Rep. 7(4):359-61 (2013).

Reiterative membranous proliferation with giant-cell deposits may followsome cases of cataract surgery. One report addresses the outcomes of a72-year-old Japanese woman and a 67-year-old Japanese man who underwentAcrySof IOL (SA60AT) implantation in their eyes (both eyes in the firstcase and the left eye in the second case) for the treatment of cataractand vitreous opacity with uveitis. Although intraocular inflammationseemed to be successfully controlled, the number of giant-cell depositson the posterior surface of the posterior capsule was graduallyincreased with the development of posterior capsular opacification in 5and 9 months, respectively, and neodymium-doped yttrium-aluminum-garnet(Nd:YAG) laser capsulotomy was required. Iwase, T., “ReiterativeMembranous Proliferation With Giant-Cell Deposits on Hydrophobic AcrylicIntraocular Lenses After Triple Procedures in Eyes with Cataracts andUveitis,” Cutan Ocul Toxicol. 29(4):306-11 (2010).

A report of 11 cases of intraocular inflammation after intravitrealinjection indicates another suitable use of the present invention. Onlyone of these cases involved infectious endophthalmitis with retinalabscess, with all others involving toxic vitreitis. Seven eyes exhibitedhypopyon and five disseminated retinal hemorrhages. The toxic reactionoccurred within 48 hours after injection, whereas in the endophthalmitiscase, it occurred after 72 hours. The cause of this reaction wasbelieved by the reporting authors to be the particular syringe brandused. After changing to another syringe brand, no further cases of toxicvitreitis occurred during the next 6 months. Ness, T., et al., “ToxicVitreitis Outbreak After Intravitreal Injection,” Retina. 30(2):332-8(2010).

A synechia is an eye condition where the iris adheres to either thecornea (i.e., anterior synechia) or lens (i.e., posterior synechia), andinstances of this condition following surgical procedures may beinhibited by the present invention. Synechiae can be caused by oculartrauma, iritis or iridocyclitis and may lead to certain types ofglaucoma. Topical corticosteroids have conventionally been used tosubdue the inflammation. Wikipedia contributors, “Synechia (eye),”Wikipedia, The Free Encyclopedia,http://en.wikipedia.org/wiki/Synechia_(eye), accessed Nov. 23, 2014.

The present invention may also be used to inhibit postoperativeintraocular fibrin formation. The anti-inflammatory effect of 0.1%diclofenac sodium on anterior inflammation after cataract surgery hasbeen reported. Fibrin precipitation after surgery in patients withoutsystemic or ocular disease was markedly less when diclofenac sodiumophthalmic solution was used in combination with topicalcorticosteroids. There was also a reduction in fibrin precipitation inother patients, especially in those with diabetes mellitus, primaryangle-closure glaucoma, and exfoliation syndrome. Matsuo, K., et al.,“Clinical Efficacy of Diclofenac Sodium on Postsurgical InflammationAfter Intraocular Lens Implantation,” Refract Surg. 21(3):309-12 (1995).

Four cases of incisional complications following pars plana vitrectomyillustrate a utility of the present invention for the inhibition ofincisional fibrosis. As reported, in each instance excessive fibrosisoccurred at the wound site. In one patient, the disorder was mild anddid not lead to clinical difficulties during his lifetime; however, inthe three severe cases the eyes were lost secondary to intraocularorganization (fibrotic changes) and phthisis bulbi. Possiblecontributing factors include diabetes mellitus, excessive trauma andnecrosis at the wound site, postoperative inflammation, and vitreousinvolvement in the wound. Kreiger, A. E., “Incisional Complications inPars Plana Vitrectomy,” Mod Probl Ophthalmol. 18:210-23 (1977).

The present invention may be useful for treating choroidalneovascularization and other complications following surgical treatmentfor macular holes. In a reported study of complications of vitrectomysurgery for full-thickness macular holes, posterior segmentcomplications were noted in 39 eyes (41%). The incidence of retinalpigment epithelium alteration and retinal detachment were 33% and 11%,respectively. One case of retinal detachment due to a giant retinal tearresulted in a visual acuity of light perception. Other complicationsincluded a reopening of the macular hole in two eyes (2%), cystoidmacular edema in one eye (1%), a choroidal neovascular membrane in oneeye (1%) and endophthalmitis in one eye (1%). Banker, A. S.,“Vision-Threatening Complications of Surgery for Full-Thickness MacularHoles. Vitrectomy for Macular Hole Study Group,” Ophthalmology.104(9):1442-52 (1997). A pilot study has been reported that suggeststhat topical ketorolac may supplement the activity of intravitrealranibizumab in reducing a mean six-month change in central macularthickness in choroidal neovascularization. Russo, A., et al., “ARandomised Controlled Trial of Ranibizumab With and Without KetorolacEyedrops for Exudative Age-Related Macular Degeneration,” Br JOphthalmol. 97(10): 1273-6 (2013).

Choroidal effusion, which is an abnormal accumulation of fluid in thesuprachoroidal space, is a common complication of glaucoma surgery andmay suitably be inhibited by the practice of the present invention.Choroidal effusion may also arise from other intraocular surgicalprocedures as well as a number of conditions, including inflammatory andinfectious diseases, trauma, neoplasms, drug reactions, and venouscongestion. Idiopathic causes fall under the umbrella of uveal effusionsyndrome, a rare condition usually considered a diagnosis of exclusion.Reddy, A. C., M.D, “Diagnosis and Management of Choroidal Effusions,”http://www.aao.org/publications/eyenet/201211/pearls.cfm?RenderForPrint=1&,accessed Nov. 23, 2014.

Hypopyon is seen as yellowish exudate in the lower part of the anteriorchamber of the eye and is formed of inflammatory cells. It is aleukocytic exudate and is a sign of inflammation of the anterior uveaand iris, i.e., iritis, which is a form of anterior uveitis. Hypopyonhas been reported in a patient with rheumatoid arthritis undergoingphacoemulsification. This 70-year-old woman was on a maintenance dose ofsystemic methylprednisolone at the time of uneventfulphacoemulsification in the left eye. She developed a sterile hypopyon onthe first postoperative day, which was treated aggressively with topicaland systemic therapy, resulting in a gradual resolution of theinflammatory response. The patient subsequently had phacoemulsificationin the right eye. The only significant difference in the preoperativemanagement this time was that the patient received topical ofloxacin andketorolac four days before surgery. The postoperative inflammatoryresponse was much more controlled. The patient was continued onketorolac and prednisolone acetate, resulting in the usual postoperativeinflammatory response. Caronia, R. M., “Antiinflammatory Effect ofPreoperative Ketorolac in Phacoemulsification,” J Cataract Refract Surg.28(10):1880-1 (2002). This report suggests that the present inventionmay have utility for inhibition of hypopyon following ocular surgery.

Predisposing Conditions

The present invention also provides a method for inhibiting apostoperative inflammatory condition following an ophthalmologicsurgical procedure by identifying a subject with a physiologic risk ofsuffering from a postoperative inflammatory condition and administeringintraocularly to the subject during an ophthalmologic surgical procedurea solution including a nonsteroidal anti-inflammatory drug (NSAID) andan alpha-1 adrenergic receptor agonist mydriatic agent in an intraocularirrigation carrier, wherein the NSAID and the mydriatic agent areincluded in the solution in amounts sufficient for the inhibition of thepostoperative inflammatory condition.

Small pupil size during surgery is also associated with increased riskof intraoperative complication. (Artzen 2009); (Zare 2009). Studies haveidentified risk factors to help surgeons predict which patients may beat risk of a complication during surgery. Advanced age, previous ocularsurgery, and diabetes with ophthalmic manifestations are amongpatient-related factors that have been associated with increased risk ofintraoperative complication. (Greenberg 2011). Individuals with diabetesmellitus (DM) are often predisposed to developing cataracts; over 25% ofcataract patients are estimated to also have concomitant DM. NationalDiabetes Clearing House, diabetes.niddk.nih.gov, Accessed on Sep. 30,2012; Ostri C., et al., “Phacoemulsification cataract surgery in a largecohort of diabetes patients: visual acuity outcomes and prognosticfactors,” J Cataract Refract Surg 37(11):2006-2012 (2011). Individualswith DM who undergo cataract surgery have a greater propensity towardsintraoperative miosis than individuals without DM. This may lead to morepostoperative complications such as development of postoperative cystoidmacular edema, worsening diabetic macular edema, progression toproliferative diabetic retinopathy, and the development of rubeosisiridis. Oetting, T., “Complicated cataract cases. Cataract surgery anddiabetes,” ASCRS Eye World,http://www.eyeworld.org/article-cataract-surgery-and-diabetes, AccessedNov. 25, 2014.

Systemic diseases, intraoperative complications and preexisting ocularconditions are risk factors that influence the development of CME.(Loewenstein 2010). Systemic risk factors for postsurgical CME includediabetes mellitus, which promotes the development of CME even in theabsence of diabetic retinopathy. Schmier J., et al., “Evaluation ofcosts for cystoid macular edema refractory to topical medications,”Ophthalmology 104:2003-2008 (1997). Systemic hypertension apparentlyincreases the incidence of postsurgical CME. Flach, A., “The incidence,pathogenesis and treatment of cystoid macular edema following cataractsurgery,” Trans Am Ophthalmol Soc 96:557-634 (1998). Systemichypertension is also a risk factor for retinal vein occlusion, whichitself increases CME. (Loewenstein 2010).

Certain surgical complications also raise the risk of CME. Rupture ofthe posterior capsule, as well as secondary capsulotomy, including YAGcapsulotomy, are associated with a higher rate of CME. Vitreous lossincreases the prevalence of CME by 10-20%. Iris incarceration is anadditional risk factor for CME, as are certain types of intraocularlenses, specifically iris-fixated IOLs and anterior chamber IOLs.(Loewenstein 2010). A review of patients with CME following pars planavitrectomy for retained lens fragments demonstrated that 8% of eyes witha sulcus-fixated posterior chamber IOL implanted at cataract extractionand 46% of eyes with aphakia or an anterior chamber IOL developed CME.Cohen, S., et al., “Cystoid macular edema after pars plana vitrectomyfor retained lens fragments,” J Cataract Surg 32:1521-1526 (2006).

Certain preexisting conditions also increase the risk of postsurgicalCME. These conditions may compromise the integrity of the blood-retinalbarrier and boost inflammatory activity. These include uveitis, in whichCME is the most important cause for poor visual outcomes followingcataract surgery. (Loewenstein 2010). As noted above, preoperativediabetic retinopathy considerably increases the risk of onset andpersistence of CME (Iliff, W., “Aphakic cystoid macular edema and theoperating microscope: is there a connection?” Trans Am Ophthalmol Soc83:476-500(1985)), while a history of retinal vein occlusion andepiretinal membrane (ERM) also predict development of CME. Henderson,B., et al., “Clinical pseudophakic cystoid macular edema. Risk factorsfor development and duration of treatment,” J Cataract Refract Surg33:1550-1558 (2007). The topical use of latanoprost in glaucoma patientshas been reported in association with pseudophakic CME. Warwar, R., etal., “Cystoid macular edema and anterior uveitis associated withlatanoprost use. Experience and incidence in a retrospective review of94 patients,” Ophthalmology 105:263-268 (1998).

In accordance with an aspect of the present invention, a subject to betreated with the NSAID and an alpha-1 adrenergic receptor agonistsolution of the invention is identified as having an elevated risk of apostoperative inflammatory condition because of a preoperativephysiologic condition or characteristic including small pupil diameter(e.g., a dilated preoperative pupil diameter of less than 6 mm), floppyiris syndrome, uveitis, retinal vein occlusion, epiretinal membrane,advanced age (e.g., over 65, elderly or geriatric), diabetes mellitus,diabetic macular edema, diabetic retinopathy, macular degeneration, orsystemic hypertension; a preoperative treatment history includingprevious ocular surgery or pharmacologic treatment with an α1-adrenergicreceptor antagonist or latanoprost; surgical trauma including posteriorcapsule rupture, secondary capsulotomy, iris incarceration, retainedlens material, or vitreous loss; and the surgical placement of nylonsutures, iris-fixated intraocular lens or an anterior chamberintraocular lens. As used herein, “elevated risk” of a postoperativeinflammatory condition refers to a subject whose risk of experiencing apostoperative inflammatory condition following an ophthalmologicprocedure is greater than the mean incidence rate of the samepostoperative inflammatory condition in healthy subjects who do not haveany predisposing risk characteristics that are undergoing the sameprocedure.

Subjects at elevated risk of postoperative inflammation may beidentified by the surgeon in advance of surgery as having an elevatedrisk of postoperative inflammation based on the patient's preoperativephysiologic condition or characteristic or preoperative treatmenthistory, or the planned placement of sutures or intraocular devices thatare associated with an enhanced incidence of postoperative inflammation.Once identified, the surgeon may administer the solution of the presentinvention during the operative procedure to preemptively decrease orreduce the incidence or severity of postoperative inflammation.Alternately the surgeon may prophylactically administer the solution ofthe present invention during the operative procedure to address anenhanced risk of postoperative inflammation that may be identifiedduring the procedure due to the nature of surgical trauma, e.g.,posterior capsule rupture, secondary capsulotomy, iris incarceration,retained lens material, or vitreous loss, or unplanned use of sutures ordevices that are associated with an enhanced incidence of postoperativeinflammation.

Pharmacologic Agents

A broad variety of ophthalmologic surgical procedures induce intraocularinflammation. As evidenced by the above described paracentesis study,once the inflammatory cascade is initiated, prostaglandin levels remainelevated for up to seven hours. The method of the present inventionprovides for the intraoperative delivery of a combination of an NSAIDand an alpha-1 adrenergic receptor agonist mydriatic agent. In apreferred embodiment of the invention, the NSAID is ketorolac and thealpha-1 adrenergic receptor agonist mydriatic agent is phenylephrine.

The impact of NSAIDs in inhibiting the formation of prostaglandin bycyclooxygenase (COX) enzymes has been shown in several studies to havean important impact on prevention of CME. Wolf, E. J., et al.,“Incidence of visually significant pseudophakic macular edema afteruneventful phacoemulsification in patients treated with nepafenac,” JCataract Refract Surg 33:1546-1549 (2007); Cervantes-Coste, G., et al.,“Inhibition of surgically induced miosis and prevention of postoperativemacular edema with nepafenac,” Clin Ophthalmol 3:219-226(2009);Donnenfeld, E. D., et al., “Preoperative ketorolac tromethamine 0.4% inphacoemulsification outcomes: pharmacokinetic-response curve,” JCataract Refract Surg. 32:1474-1482 (2006).

Suitable non-steroidal anti-inflammatory drugs (NSAIDs) for use in thepresent invention include flurbiprofen, suprofen, diclofenac,ketoprofen, ketorolac, indomethacin, nepafenac and bromfenac. Apreferred NSAID is ketorolac. As used herein, “ketorolac” meansketorolac in a salt form, such as ketorolac tromethamine[(+/−)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylicacid:2-amino-2(hydroxymethyl)-1,3-propanediol (1:1)]. Ketorolac in oneformulation of the present invention is included as the ketorolactromethamine salt[(+/−)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylicacid:2-amino-2(hydroxymethyl)-1,3-propanediol (1:1)]. Ketorolac is amember of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatorydrugs. Ketorolac HCL is a racemic mixture of the R-(+) and S-(−)enantiomers that may exist in three crystal forms, all of which areequally soluble in water. Ketorolac is a nonsteroidal anti-inflammatorythat inhibits both cyclooxygenase enzymes (COX-1 and COX-2), and whenused in accordance with the present invention results in a decrease intissue concentrations of prostaglandins to reduce pain due to surgicaltrauma. Ketorolac, by inhibiting prostaglandin synthesis secondary toocular surgical insult or direct mechanical stimulation of the iris,also prevents surgically induced miosis when used in accordance with thepresent invention.

Suitable alpha-1 adrenergic receptor agonists for use as mydriaticagents in the present invention include, for example, phenylephrine,epinephrine, oxymetazoline and naphazoline. A preferred alpha-1adrenergic receptor agonist is phenylephrine. As used herein,“phenylephrine” means phenylephrine in a salt form, such asphenylephrine HCL [(−)-m-Hydroxy-a-[(methyl amino)methyl]benzyl alcoholhydrochloride]. Phenylephrine is an alpha-1 adrenergic receptor agonistand, in the eye, acts as a mydriatic agent by contracting the radialmuscle of the iris.

In accordance with the present invention, the NSAID and alpha-1adrenergic receptor agonist solution is administered intraocularly byirrigation and/or injection during the procedure to maintain pupildiameter by promoting mydriasis and inhibiting miosis, thereby reducingsurgical trauma to the iris and intraocular structures manipulatedthrough the iris. Thus the local intraocular presence of both amydriatic agent (e.g., phenylephrine) and an anti-miotic agent (e.g.,ketorolac) during the surgical procedure provide complimentarymechanisms to preemptively limit trauma-induced inflammation during theprocedure. The in vivo study using paracentesis in a rabbit model ofsurgical trauma described above (Graff 1998) demonstrates that,following ocular surgical trauma, prostaglandin levels remain elevatedfor a period of up to seven hours. The in vivo study in dogs todetermine the concentrations of ketorolac in the retina and other oculartissues following the intracameral administration of a phenylephrine andketorolac solution, described in Example 2 below, demonstrates that theintraoperative uptake of ketorolac by retina and other ocular tissues issurprisingly at levels sufficient to inhibit COX-1 and COX-2 levels byat least 90% in ocular tissues for at least 8 hours following drugadministration, and by at least 85% in ocular tissues for at least 10hours following drug administration. Thus the present invention inhibitsinflammation during the surgical procedure, both by reducing traumathrough complimentary mydriatic and anti-miotic effects and bypreemptively inhibiting prostaglandin release, and continues to inhibitinflammation during the period when postsurgical cyclooxygenase levelsare most elevated.

Formulations

The NSAID and alpha-1 adrenergic receptor agonist are contained in anaqueous solvent as a carrier to provide a drug composition or solution.The aqueous carrier is suitably water for injection (WFI), which is asterile, solute-free preparation of distilled water. Alternately, otheraqueous carriers that are not harmful to intraocular tissues and whichwould not adversely affect the stability of the formulation may be used,such as deionized water, or, after first evaluating for potential impacton stability, saline or a balanced salt solution such as that describedbelow.

The solution of the NSAID and alpha-1 adrenergic receptor agonist of thepresent invention is suitably adjusted to a pH from 5.8 to 6.8, andpreferably to about 6.3. Sodium hydroxide and hydrochloric acid may beadded as required to adjust the formulation to this pH. The desired pHis suitably maintained by use of a buffering system. One such suitablesystem is a citrate buffer, including citric acid monohydrate and sodiumcitrate dehydrate, and another suitable system is a sodium phosphatebuffer, including dibasic sodium phosphate and monobasic sodiumphosphate. Either buffer system may be used at an appropriateconcentration in the range of 10 mM to 100 mM, and suitably may be 20mM. As described below in Example 1, sodium citrate is a preferredbuffer for use in a preservative- and antioxidant-free formulation. Thecitric acid in the citrate buffer, which has the ability to chelatedivalent cations and can thus also prevent oxidation, provides anantioxidant effect as well as a buffering effect. As used herein, theterm “antioxidant free” precludes the use of other antioxidants but doesnot preclude the use of a buffering agent, such as citric acid, that isincluded as part of the buffering system.

The NSAID and alpha-1 adrenergic receptor agonist solution of thepresent invention, e.g., a phenylephrine and ketorolac combination drugsolution, is suitably diluted into an intraocular irrigation solution byinjection into a bag, bottle or other container of an intraocularirrigation solution prior to administration by intraocular irrigation orinjection. Suitable intraocular irrigation solutions include saline,lactated Ringer's, balanced salt solution or any other irrigationsolution that is compatible with the aqueous formulation and not harmfulto ocular tissues. One suitable intraocular irrigation carrier includesone or more, and preferably all, of the following adjuvants: sufficientelectrolytes to provide a physiological balanced salt solution; acellular energy source; a buffering agent; and a free-radical scavenger.One suitable solution (referred to in the examples below as a “balancedsalt solution” or “BSS” includes: electrolytes of from 50 to 500millimolar sodium ions, from 0.1 to 50 millimolar potassium ions, from0.1 to 5 millimolar calcium ions, from 0.1 to 5 millimolar magnesiumions, from 50 to 500 millimolar chloride ions, and from 0.1 to 10millimolar phosphate; bicarbonate as a buffer at a concentration of from10 to 50 millimolar; a cellular energy source selected from dextrose andglucose, at a concentration of from 1 to 25 millimolar; and glutathioneas a free-radical scavenger (i.e., antioxidant) at a concentration offrom 0.05 to 5 millimolar.

One example of a suitable method of diluting and administering thepreferred phenylephrine and ketorolac composition of the presentinvention utilizes the formulation of the present invention described inTable 1 below. An aliquot of 4.5 mL of this solution, including 4.0 mLas the intended quantity for single use and 0.5 mL of overfill, iscontained within a sterile closed single-use vial and is intended foradmixture with irrigation solution for administration during intraocularsurgery. From the vial, 4 mL is withdrawn by syringe and mixed with 500mL of BSS by injection into a 500-mL bag or bottle of BSS to provide afinal concentration of 483 μM phenylephrine and 89 μM ketorolac in theirrigation solution for local delivery to the eye.

In another aspect of the invention, a sterile liquid pharmaceuticalformulation for irrigation may be provided in which the phenylephrineand ketorolac are already admixed within an intraocular irrigationcarrier, such that it has been diluted to the concentration of eachactive pharmaceutical ingredient desired for local delivery tointraocular tissues during surgery, and contained within a sterile bag,bottle or other irrigation container. For example, such a formulationfor irrigation may include phenylephrine at a concentration of from 30to 720 μM and ketorolac at a concentration of from 10 to 270 μM, orpreferably may include the phenylephrine at a concentration of from 90to 720 μM and the ketorolac at a concentration of from 44 to 134 μM.

As described above, an exemplary stable, liquid pharmaceuticalformulation of the present invention includes phenylephrine andketorolac in a buffered aqueous carrier. Suitable concentrations ofphenylephrine in the combination drug compositions of the presentinvention range from 10 mM to 500 mM, and preferably from 45 mM to 112mM. Suitable concentrations of ketorolac in the combination drugcompositions of the present invention range from 2 mM to 75 mM, andpreferably from 8.5 mM to 24 mM. A buffer system, such as a sodiumcitrate buffer system, is suitably included at a concentration of from10 to 100 mM, and preferably at about 20 mM. An exemplary formulationfor use in accordance with the present invention is set forth in Table 1below. Sodium hydroxide and/or hydrochloric acid may be added whenpreparing the formulation if necessary to adjust the pH to about 6.3.

TABLE 1 Example Formulation Representative Diluted Dosing ComponentConcentration (USP) added Preferred Suitable (μM) to water forConcentration Concentrations Pre- Suit- injection mg/mL mM mg/mL mMferred able Phenylephrine 12.37 60.75 9.2-15.5   45-76 483 240-720 HClKetorolac 4.24 11.25 3.2-5.3  8.5-14 89  44-134 tromethamine Citric acid0.24* 0.12-1.20** monohydrate Sodium citrate 5.48* 2.74-27.4** dihydrate*Corresponding to a 20 mM citrate buffer. **Corresponding to a 10 mM to100 mM citrate buffer.

The amounts of pharmaceutically active ingredients included in theformulation can be expressed in molar ratios. The molar ratio ofphenylephrine to ketorolac may range from 1:1 to 13:1, and more suitablymay range from 3:1 to 10:1. An exemplary molar ratio of phenylephrineand ketorolac as represented in Table 1 above is 5.4:1 of phenylephrineto ketorolac.

Following dilution of this exemplary formulation of the presentinvention into an intraocular irrigation carrier for local delivery, thedosing concentration of phenylephrine may be from 3 to 7,200 μM, moresuitably from 30 to 720 μM, more preferably from 90 to 720 μM, stillmore preferably from 240 to 720 μM, and most preferably about 483 μM.Following dilution of the formulation of the present invention into anintraocular irrigation carrier for local delivery, the dosingconcentration of ketorolac may be from 3 to 900 μM, more suitably from10 to 270 μM, more preferably from 44 to 134 μM, still more preferablyfrom 30 to 90 μM, and most preferably about 90 μM.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “anexcipient” includes a plurality of such excipients and equivalentsthereof known to those skilled in the art, and so forth. The term“about” as used herein is understood to mean that there can be variationin a stated condition or amount that can be to 5%, 10%, 15% or up to andincluding 20% of the given value.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.All citations are incorporated herein by reference.

EXAMPLES Example 1 Clinical Studies Evaluating Phenylephrine1%/Ketorolac 0.3% in Cataract Surgery and Intraocular Lens Replacementfor Maintenance of Mydriasis and Prevention of Postoperative Pain

This example describes two Phase 3 clinical studies performed toevaluate the efficacy and safety of phenylephrine 1% and ketorolac 0.3%injection formulated as described in Table 1 above when used for themaintenance of mydriasis during, and prevention of postoperative painfollowing, cataract surgery and intraocular lens (IOL) replacement.

Methods

Two pivotal, multi-center, randomized, parallel-group, double-masked,placebo-controlled phase 3 studies (Study 1 and Study 2) that wereconducted to support the use of phenylephrine 1% and ketorolac 0.3%injection (OMS302) for maintaining intraoperative mydriasis, preventingintraoperative miosis, and reducing early postoperative ocular painassociated with cataract surgery and IOL replacement. A total of 20sites in the United States and Netherlands enrolled subjects in thesestudies.

Subjects were randomized to receive either OMS302 or placebo. A singleadministration of study drug, OMS302 (483 μM phenylephrine and 89 μMketorolac formulated in 20 mM sodium citrate buffer) or placebo (20 mMsodium citrate buffer), was added to balanced salt solution (BSS, 500mL) and administered intracamerally as part of the standard irrigationsolution during the procedure. Postoperative evaluations were conductedfor up to 14 days (Study 1) or 90 days (Study 2); integrated safetyanalyses were limited to data collected up to 14 days post-surgery. Allsubjects (OMS302-treated and placebo-treated) in the studies receivedstandard-of-care preoperative topical mydriatic and anesthetic agents.

Two co-primary endpoints were pre-specified for the integratedanalyses: 1) intraoperative pupil diameter during surgery and 2) ocularpain during the early postoperative period following surgery. Eachsubject's surgical procedure was video recorded and change in pupildiameter was measured at one-minute intervals from time of incision(surgical baseline) until wound closure (surgical end) by a single,masked central reader. Postoperative ocular pain was measured using asubject-assessed visual analog scale (VAS) at 2, 4, 6, 8, and 10-12hours after surgery and on Days 2, 7, and 14.

Key secondary endpoints included pupil diameter <6 mm at end of corticalclean-up, pupil diameter <6 mm at any time during surgery,intraoperative pupillary constriction of ≥2.5 mm, moderate-to-severeocular pain (VAS ≥40) at any time point assessed within the first 12postoperative hours, and no ocular pain (VAS=0) at all time pointsassessed within the first 12 postoperative hours. Post-hoc secondaryanalyses included categorization of subjects' intraoperative pupilconstriction and analgesic use on day of surgery.

Statistical Analysis

Each study was conducted independently. The sample size calculations forthe two studies were identical: a total of 400 subjects (200 subjectsper treatment arm) in each study provided 99% power to detect adifference of 0.6 mm (standard deviation [SD]: 0.7 mm) in meanarea-under-the-curve (AUC) pupil diameter change from baseline and 96%power to detect a difference of 5.0 mm (SD: 13.3 mm) in mean AUC ofocular pain VAS during the first 12 postoperative hours using atwo-sided t-test with α=0.05.

The mean AUC pupil diameter change from baseline during surgery wascalculated as follows: 1) the trapezoidal rule was used to calculate theAUC of the pupil diameter from surgical baseline to wound closure, 2)the result was divided by time of the last pupil diameter value toobtain the mean AUC, and 3) the baseline pupil diameter was subtractedfrom the mean AUC. The AUC of ocular pain VAS during the first 10-12postoperative hours was also calculated using the trapezoidal rule withthe mean AUC defined as the AUC divided by the number of hours from thefirst VAS score to the last VAS score within this time frame. For bothprimary endpoints, a generalized Cochran-Mantel-Haenzel (CMH) teststratified by randomization strata was used to compare the two treatmentarms for the two studies combined (LaVange, et al. 2005).

Treatment comparisons for all secondary efficacy analyses presented wereperformed using Chi-square test or Fisher's exact test if the frequencyin a category was less than five. All statistical analyses wereperformed using SAS software (version 9.3, SAS Institute, Inc., CaryN.C.).

Results—Efficacy

OMS302 was superior to placebo in maintaining mydriasis during cataractsurgery or IOL replacement procedures. Among 759 subjects with usablevideo images for determination of pupil diameter, the mean AUCchange-from-baseline in pupil diameter was 0.08 mm for the OMS302 group(n=379) compared to −0.50 mm for the placebo group (n=380) and theCMH-weighted mean difference (OMS302—placebo) (standard error [SE]) was0.58 mm (0.04) (95% confidence interval [CI]: 0.51, 0.65; p<0.0001).Following initiation of surgery, baseline pupil diameter was maintainedwith OMS302 treatment while progressive miosis was observed with placebotreatment (FIG. 1). Results of secondary efficacy analyses evaluatingincidence of subjects with pupil diameter <6 mm at completion ofcortical clean up and at any time during surgery also favored OMS302treatment (Table 2). The proportions of subjects with pupil diameter <6mm at the time of cortical clean-up completion, pupil diameter <6 mm atany time during surgery, and degree of intraoperative pupillaryconstriction of ≥2.5 mm were all significantly lower amongOMS302-treated subjects than placebo-treated subjects (p<0.0001 for eachendpoint). Considerably fewer OMS302-treated subjects than placebosubjects experienced intraoperative pupil constriction greater than 1 mm(FIG. 2).

TABLE 2 Supportive Efficacy Endpoints Placebo OMS302 (N = 405) (N = 403)Pupil Diameter Endpoints (includes subjects with readable video data)Subjects with <6 mm at cortical clean-up  87/380 (22.9%) 15/379 (4.0%)p-value^(a) <0.0001 Subjects with <6 mm at any time during surgery161/380 (42.4%) 37/379 (9.8%) p-value^(a) <0.0001 Subjects with degreeof pupillary constriction^(b) ≥2.5 mm 103/380 (27.1%)  8/379 (2.1%)p-value^(a) <0.0001 Ocular Pain Endpoints (includes subjects withcomplete VAS scores) Subjects pain free (VAS = 0) at all time points^(c) 69/403 (17.1%) 104/403 (25.8%) p-value^(a)  0.0027 Subjects withmoderate to severe pain (VAS ≥ 40)  57/403 (14.1%) 29/403 (7.2%) at anytime point p-value^(a)  0.0014 Analgesic use on day of surgery 140/403(34.7%) 99/403 (24.6%)  p-value^(a) 0.002 ^(a)Chi-Square test^(b)Maximum decrease in pupil diameter from baseline during surgery^(c)Subjects with missing VAS during 12 hours postoperatively areconsidered as not being pain-free

Treatment with OMS302 was associated with a significant reduction inearly postoperative ocular pain compared to placebo. Ocular pain VASscores during the first 12 hours postoperatively were more than 50%lower for the OMS302 group (mean AUC=4.16 mm, n=403) than for theplacebo group (mean AUC=9.06 mm, n=403). The CMH-weighted meandifference (OMS302—placebo) (SE) in AUC of ocular pain scores was −4.89mm (0.80) (95% CI: −6.46, −3.31; p<0.001). Mean VAS scores were loweramong subjects treated with OMS302 at each postoperative time point(FIG. 3). The proportion of subjects who were ocular pain free (VAS=0)at all postoperative time points was significantly higher for OMS302compared to placebo (25.8% vs 17.1%, respectively, p=0.0027; Table 2)and the proportion of subjects with moderate-to-severe ocular pain (VAS≥40) at any postoperative time point was significantly lower for OMS302compared to placebo (7.2% vs 14.1%, respectively, p=0.0014). Notably, inaddition to lower VAS pain scores in the OMS302 group, use of analgesicson the day of surgery was also significantly lower among subjectstreated with OMS302 compared to placebo (24.6% vs 35.1%, respectively,p=0.0010).

Results—Safety

Of the 808 subjects (403 OMS302, 405 placebo) included in the pooledsafety analyses, 513 (63.5%) experienced at least one treatment-emergentadverse event (TEAE). The proportion of subjects reporting TEAEs wasslightly lower among subjects receiving OMS302 (242/403 [60.0%]) thanplacebo (271/405 [66.9%]). The majority of TEAEs were mild or moderatein severity. Only one serious adverse event was reported in the twostudies. This event (death due to electrocution deemed unrelated tostudy drug) was also the only event that resulted in prematurediscontinuation from the studies.

The most frequently-reported TEAE consisted of eye pain (reported by35.1% of subjects overall), eye inflammation (15.5%), anterior chamberinflammation (8.7%), headache (7.9%), intraocular pressure increased(4.1%), posterior capsule opacification (4.1%), ocular discomfort(4.1%), photophobia (4.0%), corneal edema (2.8%), vision blurred (2.7%),conjunctival hyperemia (2.6%), and foreign body sensation in the eyes(2.2%). These events were reported by similar proportions of subjects ineach treatment group with the exception of eye pain, headache, oculardiscomfort, photophobia, and vision blurred, which were experienced byslightly more (>1% difference between treatment groups) placebo subjects(4.0%, 9.4%, 5.2%, 4.9%, 4.2%, respectively) than OMS302 subjects (3.3%,6.5%, 3.0%, 3.0%, 1.2%, respectively). Increased intraocular pressurewas the only common TEAE occurring in a slightly greater proportion (>1%difference) of OMS302-treated subjects (4.7% OMS302 vs 3.5% placebo).

Severe TEAEs were experienced by a total of 18 subjects (13 [3.2%]placebo subjects and 5 [1.2%] OMS302 subjects). Except for the event ofaccidental electrocution experienced by a subject treated with OMS302,all severe TEAEs consisted of eye disorders, including eye inflammation(n=11), anterior chamber inflammation (n=2), and conjunctival edema,corneal edema, conjunctival hyperemia, eye pain, and photophobia (n=1each). Of note, all severe TEAEs considered to be related to studytreatment occurred among subjects receiving placebo. These eventsincluded two instances of anterior chamber inflammation, and events of,corneal edema, eye pain, photophobia, eye inflammation, and conjunctivalhyperemia.

Increased intraocular pressure was observed for several subjects in bothtreatment groups following surgery. By Day 2, increases compared tobaseline were less notable; however, the abnormality persisted in somesubjects through the end of the study. No notable TEAEs were reported inthese subjects and no differences in the proportions of subjects withincreased intraocular pressure were observed between the two treatmentgroups on each evaluation day. In addition, no differences betweentreatment groups were observed for any other serial assessments ofsafety (i.e., vital signs or ophthalmological exams).

Conclusions

OMS302 was superior to placebo for the maintenance of mydriasis during,and reduction of ocular pain following, IOL replacement. The meanarea-under-the-curve (AUC) change from baseline in pupil diameter was0.08 mm for OMS302 compared to −0.50 mm for placebo (p<0.0001). Mean AUCof subject ocular pain visual analog scale (VAS) scores within 12 hourspostoperatively were over 50% lower for OMS302 (mean AUC=4.16 mm) thanplacebo (mean AUC=9.06 mm, p<0.001). Results of all secondary efficacyanalyses demonstrated a significant treatment effect associated withOMS302. Treatment-emergent adverse events were as expected for apopulation undergoing IOL replacement; no clinically significantdifferences in safety measures were observed between treatment groups.

The integrated results of these two pivotal phase 3 studies demonstratethe superiority of OMS302 compared to placebo in maintaining pupildiameter and preventing miosis during, and preventing postoperativeocular pain following, cataract extraction with lens replacement orrefractive lens exchange procedures, even though all subjects receivedstandard preoperative topical mydriatics and anesthetics. The efficacyanalyses were robust; AUC analyses of the co-primary endpoints for theintegrated analysis, performed to show the aggregate effect of OMS302 onpupil diameter during surgery and early postoperative pain, and allsecondary efficacy analyses were supportive. Furthermore, OMS302 was notassociated with any new or additional toxicities compared to placebo.Common adverse events and safety findings (e.g., increased intraocularpressure) observed in clinical studies of OMS302 performed to date areconsistent with events commonly reported among patients undergoing theseprocedures, and no clinically significant differences between treatmentgroups were observed.

Example 2 Ocular Tissue Distribution of Ketorolac FollowingAdministration of Phenylephrine 1%/Ketorolac 0.3% to Dogs DuringIntraocular Lens Replacement

This example describes the results of an in vivo study in dogs todetermine the concentrations of ketorolac in the retina and other oculartissues following the intracameral administration of phenylephrine 1%and ketorolac 0.3% injection formulated as described in Table 1 (OMS302)during IOL replacement in dogs.

Methods

IOL replacement by phacoemulsification was performed on 20 femalebeagles. During the procedure, OMS302 was administered in BSS solutionvia irrigation and intracameral injection immediately post-procedure.The target dose level of ketorolac was 5.71 mg/eye, and the target dosevolume of OMS302 diluted in BSS solution was 250 mL per eye. Fouranimals per time point were sacrificed at 0, 2, 6, 8, and 10 hourspost-procedure. Samples of blood and aqueous humor were collected.Enucleated eyes were frozen and dissected for collection of retina,retinal pigmented epithelium-choroid, cornea, iris-ciliary body,vitreous humor, sclera, and lens capsule. Tissue concentrations ofketorolac were quantitated using a liquid chromatography/massspectrometry (LCMS) method. Using published IC50 values forcyclooxygenase (COX) inhibition by ketorolac (Waterbury, et. al., CurrMed Res Opin 22(6):1133-40 (2006)), estimates of percent inhibition werederived for each time point.

Results

FIGS. 4-6 illustrate the mean concentrations of ketorolac at specifiedtime points after the intracameral doses of OMS302, with FIG. 4 showingketorolac concentrations in the cornea, lens capsule, iris-ciliary body(ICB), aqueous humor, and anterior sclera; FIG. 5 showing ketorolacconcentrations in the bulbar and palpebral conjunctiva; and FIG. 6showing the ketorolac concentrations in vitreous humor, retina,choroid-RPE (peripheral), choroid-RPE (tapetum), and posterior sclera.FIG. 7 shows the mean percent inhibition of COX-1 and COX-2 in retinaltissues at t=0 through t=10 hours, based on an IC50 of 20 nM and a Ki of10 nM for COX-1 and an IC50 of 120 nM and a Ki of 60 nM for COX-2.Ketorolac concentrations in the retina were 1400±1004 ng/g immediatelyfollowing the end of IOL replacement, and 164±39 ng/g at eight hourspost-procedure, corresponding to estimated COX-1/COX-2 inhibition of99.3%/96.0% at t=0, and 98.4%/91.1% at t=8 hours. The retinal half-lifewas ˜3.8 hours. Surprisingly, tissue concentrations in aqueous humor,vitreous humor, and RPE-choroid at t=8 hours were consistent with >90%inhibition of COX-1 and COX-2. Also surprisingly, at t=10 hours, retinaltissue concentrations were 97.74% (with a standard deviation of 0.36%)for COX-1 and 87.82 (with a standard deviation of 1.75%) for COX-2. Themean plasma level of ketorolac was 4.73±1.46 ng/mL at t=0, declining toundetectable levels at t ≥2 hours.

Conclusions

In this study, the use of OMS302 during IOL replacement surgery resultedin the uptake of ketorolac by retina and other ocular tissues at levelssufficient to inhibit COX-1 and COX-2 levels in intraocular tissues bygreater than 90% for at least 8 hours, and by greater than 85% for atleast 10 hours, following drug administration in the intracameralirrigation solution, which duration of action was unexpected. Systemicexposure was low and transient.

Example 3 Clinical Study Evaluating Intracameral Ketorolac ConcentrationFollowing Topical Ketorolac Administration Prior to Cataract Surgery

This example describes the results of a clinical study to determinepostoperative intracameral concentrations of ketorolac in subjectsreceiving topical ketorolac prior to cataract surgery.

Methods

Patients undergoing cataract extraction and lens replacement (CELR) wereeligible. Written informed consent was obtained from 14 subjects, eachof whom received topical ophthalmic ketorolac according to the surgeon'susual practice, beginning one day preoperatively. Immediately prior tothe initial surgical incision, the surgeon withdrew a 100-μL sample ofaqueous humor from the operative eye with a 30-gauge tuberculin syringe.At the conclusion of CELR prior to final re-inflation of the anteriorchamber and wound closure, the surgeon withdrew another 100-μL samplefrom the anterior chamber. The ketorolac concentrations of theintracameral fluid samples were analyzed by an analytical laboratory.

Results

Thirteen of 14 subjects used four doses of ketorolac the day prior tosurgery, and one subject used three doses the day prior to surgery. All14 subjects received topical ketorolac in the surgery center on the dayof surgery. Aqueous humor samples were inadvertently not collected fromtwo subjects. The preoperative ketorolac concentrations for the 12subjects on whom samples were collected ranged from 4.9 to 369 ng/mL.The end-of-procedure samples ranged from <1.0 (the lower limits ofquantification, or LLOQ) to 6.32 ng/mL, with eight of the 12 subjectshaving ketorolac levels below the LLOQ.

Conclusions

At-home compliance with topical ketorolac was generally good, with 92.9%of subjects using topical ketorolac as directed. Following CELR, levelsof ketorolac in the aqueous humor at the end of the surgical procedurewere low, likely due to irrigation wash-out, as 66.7% of subjects had anundetectable concentration of ketorolac.

The in vivo and clinical studies of Examples 2 and 3, respectively,demonstrate that intracamerally delivering ketorolac in aketorolac/phenylephrine solution during cataract and IOL replacementsurgery should result in a pharmacologically active level of ketorolacin the eye for a substantially longer postoperative time than resultsfrom topically delivering ketorolac preoperatively, thereby providingfor sustained postoperative inflammation inhibition.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to one of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A method for inhibitinga postoperative inflammatory condition following an ophthalmologicsurgical procedure comprising: identifying a subject with an elevatedrisk of suffering from a postoperative inflammatory condition;administering intraocularly to the subject during an ophthalmologicsurgical procedure a solution including a nonsteroidal anti-inflammatorydrug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic agentin an intraocular irrigation carrier, wherein the NSAID and themydriatic agent are included in the solution in amounts sufficient tomaintain intraoperative pupil diameter by promoting mydriasis andinhibiting miosis, and a sufficient amount of the solution isadministered for uptake of an amount of the NSAID in ocular tissuessufficient for inhibition of cyclooxygenases for a period of at leastsix hours postoperatively, thereby inhibiting the postoperativeinflammatory condition.
 2. The method of claim 1, wherein the NSAID isselected from the group consisting of flurbiprofen, suprofen,diclofenac, ketoprofen, ketorolac, indomethacin, nepafenac andbromfenac.
 3. The method of claim 1, wherein the alpha-1 adrenergicreceptor agonist is selected from the group consisting of phenylephrine,epinephrine, oxymetazoline and naphazoline.
 4. The method of claim 1,where in the NSAID is ketorolac and the mydriatic agent isphenylephrine.
 5. The method of claim 4, wherein the solution comprisesphenylephrine at a concentration of from 240 to 720 μM and the ketorolacis present at a concentration of from 44 to 134 μM.
 6. The method ofclaim 1, wherein the subject is identified prior to the procedure ashaving an elevated risk of suffering from a postoperative inflammatorycondition.
 7. The method of claim 1, wherein the subject is identifiedduring the procedure as having an elevated risk of suffering from apostoperative inflammatory condition.
 8. The method of claim 1, whereina sufficient amount of the NSAID and the mydriatic agent are included inthe solution to maintain an intraoperative pupil diameter of at least6.0 mm during the procedure.
 9. The method of claim 1, wherein thesolution results in at least 90% inhibition of baseline cyclooxygenase-1and cyclooxygenase-2 activity levels in ocular tissues for a period ofat least six hours postoperatively.
 10. The method of claim 1, whereinthe solution results in at least 90% inhibition of baselinecyclooxygenase-1 and cyclooxygenase-2 activity levels in ocular tissuesfor a period of at least eight hours postoperatively.
 11. The method ofclaim 1, wherein the solution results in at least 85% inhibition ofbaseline cyclooxygenase-1 and cyclooxygenase-2 activity levels in oculartissues for a period of at least ten hours postoperatively.
 12. Themethod of claim 1, wherein the postoperative inflammatory condition isselected from the group consisting of toxic anterior-segment syndrome,cystoid macular edema, acute endophthalmitis, posterior capsuleopacification, anterior capsule contraction, herpes simplex viruskeratitis after cataract surgery, postsurgical hypotony, nylon suturetoxicity, long-term corneal endothelial cell loss after cataractsurgery, corneal edema, iris chafing, corneo-retinal inflammatorysyndrome, scleritis, episcleritis, vitreous wick syndrome,post-operational acute iridocyclitis, uveitis, epiretinal deposits aftercataract extraction, reiterative membranous proliferation withgiant-cell deposits, toxic vitreitis, posterior synechia, postoperativeintraocular fibrin formation, incisional fibrosis, complications ofmacular hole surgery, choroidal effusion, and hypopyon.
 13. The methodof claim 1, wherein the subject is at elevated risk of a postoperativeinflammatory condition because of a preoperative physiologic conditionor characteristic, a preoperative treatment history, surgical trauma, orthe surgical placement of a device that is associated with an enhancedincidence of postoperative inflammation.
 14. The method of claim 13,wherein the subject is at elevated risk of a postoperative inflammatorycondition because of a preoperative physiologic condition orcharacteristic including a preoperative dilated pupil diameter of lessthan 6 mm, floppy iris syndrome, uveitis, retinal vein occlusion,epiretinal membrane, being over 65 years of age, diabetes mellitus,diabetic macular edema, diabetic retinopathy, macular degeneration, orsystemic hypertension; a preoperative treatment history includingprevious ocular surgery or pharmacologic treatment with an alpha-1adrenergic receptor antagonist or latanoprost; surgical trauma includingposterior capsule rupture, secondary capsulotomy, iris incarceration,retained lens material, or vitreous loss; and the surgical placement ofnylon sutures, iris-fixated intraocular lens or an anterior chamberintraocular lens.
 15. The method of claim 1, wherein the solution isadministered by continuous intraocular irrigation during the procedure.16. The method of claim 15, wherein the solution is administered bycontinuous intraocular irrigation during the procedure followed byinjection of a bolus of the solution at the end of the procedure. 17.The method of claim 1, wherein the solution is administered byintraocular injection during a procedure in which another therapeuticagent is injected intraocularly.
 18. The method of claim 1, wherein thesolution is administered by intraocular injection preoperatively,intraoperatively and/or postoperatively.
 19. A method for inhibiting apostoperative inflammatory condition following an ophthalmologicsurgical procedure comprising: identifying a subject with an elevatedrisk of suffering from a postoperative inflammatory condition;administering intraocularly to the subject during an ophthalmologicsurgical procedure a solution including a nonsteroidal anti-inflammatorydrug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic agentin an intraocular irrigation carrier, wherein the NSAID and themydriatic agent are included in the solution in amounts sufficient formaintenance of intraoperative pupil diameter and inhibition of thepostoperative inflammatory condition.
 20. A method for inhibiting apostoperative inflammatory condition following an ophthalmologicsurgical procedure comprising intraocular administration during anophthalmologic surgical procedure, to a subject at risk of apostoperative inflammatory condition, a solution including anonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergicreceptor agonist mydriatic agent in an intraocular irrigation carrier,wherein the NSAID and the mydriatic agent are included in the solutionin amounts sufficient to maintain intraoperative pupil diameter bypromoting mydriasis and inhibiting miosis, and a sufficient amount ofthe solution is administered for uptake of an amount of the NSAID inocular tissues sufficient for inhibition of cyclooxygenases for a periodof at least six hours postoperatively, thereby inhibiting thepostoperative inflammatory condition.
 21. A method for reducing theincidence or severity of cystoid macular edema following anophthalmologic surgical procedure comprising: identifying a subject withan elevated risk of suffering from cystoid macular edema; administeringintraocularly to the subject during an ophthalmologic surgical procedurea solution including a nonsteroidal anti-inflammatory drug (NSAID) andan alpha-1 adrenergic receptor agonist mydriatic agent in an intraocularirrigation carrier, wherein the NSAID and the mydriatic agent areincluded in the solution in amounts sufficient for maintenance ofintraoperative pupil diameter and reduction of the incidence or severityof postoperative cystoid macular edema.